The present invention relates to the field of immunology. More specifically, novel biotechnological tools, therapeutics and phophylactics, which modulate antigen presenting cell activity are disclosed.
The mature, circulating, antigen specific cells of the immune system face a challenge that does not trouble most other cells of the body. They must find each other, and they must do it often and quickly, every time there is need of an immune response. The problem is compounded by the rarity of the communicating partners, since only about 1 in 104 circulating B lymphocytes can react to any particular antigen and the frequency of antigen specific T cells is thought to be similarly low. (Kennedy et al., J. Immuno. 96:973-980 (1966) and Vann, D. C. and Dotson, D. R., J. Immunol. 112:1149-1157 (1974)). Thus, a rare T helper cell specific for a particular pathogen needs to find an equally rare B cell specific for the same antigen. The fact that these encounters occur at all is due to the circulation patterns of these cells in lymph nodes and other specialized organs, as well as, the B cell""s ability to act as an antigen presenting cell (APC) and attract the appropriate helper by creating a surface display of MHC class II molecules loaded with peptides from the antigen the B cell has captured. (Tony, H.P. and Parker, D. C., J. Exp. Med. 161:223-241 (1985) and Lanzavecchia, A., Nature 314:537-539 (1985)).
Once a B cell has attracted the right T helper cell, it uses a family of receptor-ligand pairs such as B7, CD40, and various cytokine receptors to stimulate the T cell and receive stimuli in turn. (Foy, T. M. et al., Semin. Immunol. 6:259-266 (1994)). T killer cells cannot do this and, if the two cell exchange between rare T and B cells seems challenging enough, the problem is far worse for communication between T helpers and T killer cells where the interaction requires a third participant, an APC, that brings the T helpers and T killers together by displaying antigens to both. (Keene, J. A. and Forman, J., J. Exp. Med. 155:768-782 (1982); Mitchison, N. A. and O""Malley, C., Eur. J. Immunol. 17:1579-1583 (1987); and Bennett, S. R. et al., J. Exp. Med. 186:65-70 (1997)).
The problem is two fold. First there is the challenge of bringing together three rare circulating cells. Second, since T killers do not express the sorts of co-stimulatory molecules expressed by B cells and APCs, (and, in mice, do not express MHC class II molecules with which to present antigen to helper T cells) the question of how help is stimulated and delivered remains.
Currently, investigators believe that dendritic cells exist in only two states: resting (an xe2x80x9cimmaturexe2x80x9d state) and activated (a xe2x80x9cmaturexe2x80x9d state). In the activated state, a dendritic cell can present antigen and stimulate T helper cells, but not T killers. The successful priming of killer T cells is believed to require a three cell interaction between rare antigen loaded APCs and rare antigen specific helper T cells and killer T cells. In the model set forth by Keene and Forman, for example, the presenting cell has a rather passive relationship with the killer T cell and, like a B cell, the APC functions mainly to stimulate the helper cell, which then secretes cytokines necessary for the growth and activation of the neighboring killer T cell. (Keene, J. A. and Forman, J., J. Exp. Med. 155:768-782 (1982)).
For several reasons this picture is not completely satisfying. First, there is no guarantee that a rare T helper and an equally rare T killer should find the same APC at the same time. Because resting killers recognizing antigen become tolerant if there is no help available, many potentially useful killers would be rendered useless by the lack of immediate help. (Guerder, S. and Matzinger, P., J. Exp. Med. 176:553-564 (1992); Guerder, S. and Matzinger, P., Cold Spring Harb. Symp. Quant. Biol. 54:799 (1989); and Rees, M. A. et al., Proc. Natl. Acad. Sci. U.S.A. 87:2765-2769 (1990)). Second, the T helper would wastefully secrete its cytokines into an environment that may contain no killers to receive them. Third, killer responses to certain viruses are unimpaired by the absence of helper cells. (Tripp, R. A., et al., J. Immunol. 155:2955-2959 (1995); Buller, R. M. et al., Nature 328:77-79 (1987); Cardin, R. D. et al., J. Exp. Med. 184:863-871 (1996); Hou, S. et al., J. Virol. 69:1429-1434 (1995); Ahmed, R. et al. J. Virol. 62:2102-2106 (1988); and Leist, T. P. et al., Scand. J. Immunol. 30:679-686 (1989)). The three cell interaction model offers no explanation for the existence of these helper independent killer responses. In view of the foregoing and not withstanding the various efforts exemplified in the prior art, clearly several crucial pieces of the puzzle are missing.
In the present invention, we demonstrate that an APC, preferably a dendritic cell, can be stimulated to a third statexe2x80x94a xe2x80x9csuperactivatedxe2x80x9d state. T helper cells, some viruses, and some antigens induce the dendritic cell to manifest the superactivated state. In contrast to activated dendritic cells, superactivated dendritic cells have the ability to activate a killer T cell by forming a two cell complex having the superactivated dendritic cell and the killer T cell. Notably, the superactivated APC activates a killer cell in the absence of a T helper cell. Additionally, we have discovered that specific agents which interact with the APC superactivate the APC or block, inhibit, or prevent the activation of killer T cells by interacting with the APC. We show that through modulation of the activation state of an APC, such as a dendritic cell by, for example, administering antibodies which interact with the APC, the activation of a T cell is concordantly governed.
In embodiments of the present invention, we reveal novel biotechnological tools, prophylactics, therapeutics, and methods of use of the foregoing for modulating the activation state of an APC and thereby modulating the activation of a killer T cell. These embodiments have several uses and applications in the field of immunology, and enable one of skill in the art to manufacture novel pharmaceuticals, therapeutic and prophylactic agents, and vaccine components for the treatment and prevention of cancer, systemic infection, and autoimmune responses.